{"title":"发现以AZD9291为基础的新型缺氧激活、硝基咪唑构建的治疗人肺癌的多靶点激酶抑制剂","authors":"Tingting Jia , Ruoyang Miao , Jiankang Zhang , Huajian Zhu , Chong Zhang , Linghui Zeng , Yanmei Zhao , Weiyan Cheng , Jiaan Shao","doi":"10.1016/j.bmc.2023.117384","DOIUrl":null,"url":null,"abstract":"<div><p>A group of 4-(1-methyl-1<em>H</em>-indol-3-yl)pyrimidin-2-amine derivatives containing a hypoxia-activated nitroimidazole group were designed as EGFR inhibitors. Among this series, <strong>A14</strong> was identified as the optimal compound, exhibiting potent anti-proliferative activities against H1975 and HCC827 cells. Under hypoxic condition, the anti-proliferative activities of <strong>A14</strong> improved by 4–6-fold (IC<sub>50</sub> < 10 nM), indicating its hypoxia-selectivity. <strong>A14</strong>′s high potency may be attributed to its inhibition against multiple kinases, including EGFR, JAK2, ROS1, FLT3, FLT4 and PDGFRα, which was confirmed by binding assays on a panel of 30 kinases. Furthermore, <strong>A14</strong> exhibited good bio-reductive property and could bind with nucleophilic amino acids after being activated under hypoxic conditions. With its anti-proliferative activities and selectivity for hypoxia and oncogenic kinases, <strong>A14</strong> shows promise as a multi-target kinase inhibitor for cancer therapy.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"91 ","pages":"Article 117384"},"PeriodicalIF":3.3000,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Discovery of novel hypoxia-activated, nitroimidazole constructed multi-target kinase inhibitors on the basis of AZD9291 for the treatment of human lung cancer\",\"authors\":\"Tingting Jia , Ruoyang Miao , Jiankang Zhang , Huajian Zhu , Chong Zhang , Linghui Zeng , Yanmei Zhao , Weiyan Cheng , Jiaan Shao\",\"doi\":\"10.1016/j.bmc.2023.117384\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>A group of 4-(1-methyl-1<em>H</em>-indol-3-yl)pyrimidin-2-amine derivatives containing a hypoxia-activated nitroimidazole group were designed as EGFR inhibitors. Among this series, <strong>A14</strong> was identified as the optimal compound, exhibiting potent anti-proliferative activities against H1975 and HCC827 cells. Under hypoxic condition, the anti-proliferative activities of <strong>A14</strong> improved by 4–6-fold (IC<sub>50</sub> < 10 nM), indicating its hypoxia-selectivity. <strong>A14</strong>′s high potency may be attributed to its inhibition against multiple kinases, including EGFR, JAK2, ROS1, FLT3, FLT4 and PDGFRα, which was confirmed by binding assays on a panel of 30 kinases. Furthermore, <strong>A14</strong> exhibited good bio-reductive property and could bind with nucleophilic amino acids after being activated under hypoxic conditions. With its anti-proliferative activities and selectivity for hypoxia and oncogenic kinases, <strong>A14</strong> shows promise as a multi-target kinase inhibitor for cancer therapy.</p></div>\",\"PeriodicalId\":255,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry\",\"volume\":\"91 \",\"pages\":\"Article 117384\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2023-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0968089623002328\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089623002328","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Discovery of novel hypoxia-activated, nitroimidazole constructed multi-target kinase inhibitors on the basis of AZD9291 for the treatment of human lung cancer
A group of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine derivatives containing a hypoxia-activated nitroimidazole group were designed as EGFR inhibitors. Among this series, A14 was identified as the optimal compound, exhibiting potent anti-proliferative activities against H1975 and HCC827 cells. Under hypoxic condition, the anti-proliferative activities of A14 improved by 4–6-fold (IC50 < 10 nM), indicating its hypoxia-selectivity. A14′s high potency may be attributed to its inhibition against multiple kinases, including EGFR, JAK2, ROS1, FLT3, FLT4 and PDGFRα, which was confirmed by binding assays on a panel of 30 kinases. Furthermore, A14 exhibited good bio-reductive property and could bind with nucleophilic amino acids after being activated under hypoxic conditions. With its anti-proliferative activities and selectivity for hypoxia and oncogenic kinases, A14 shows promise as a multi-target kinase inhibitor for cancer therapy.
期刊介绍：
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.
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